The administration of nitric oxide (NO) gas via inhalation for treating patients with pulmonary hypertension is described in Zapol and Frostell's U.S. Pat. No. 5,485,827 “Methods and Devices for Treating Pulmonary Vasoconstriction and Asthma”.
At the present, nitric oxide gas is commonly used for the treatment of persistent pulmonary hypertension in the newborn and is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure (HRF) associated with clinical or echocardiographic evidence of pulmonary hypertension. In babies with HRF, blood vessels in the lungs constrict, making it difficult for the heart to pump blood through the lungs for oxygenation. Nitric oxide is a pulmonary vasodilator, which relaxes the blood vessels of the lungs in newborns whose heart and lungs could not otherwise carry enough oxygenated blood to the body tissues.
There are also other clinical applications in which NO is used to treat surface infections on the skin of a patient as described in U.S. Pat. No. 6,432,077.
U.S. Pat. No. 5,670,127 “Process for the Manufacture of Nitric Oxide” (Len-Lung Sheu) describes a method for producing nitric oxide, NO, for medical use by reacting aqueous nitric acid with gaseous sulfur dioxide in a gas-liquid contact reactor to produce 100% NO gas. It is important to note that all of the reactants used in this method are hazardous to handle and, accordingly, the process has to be strictly controlled. The NO produced by this method, which is close to 100%, is blended with an inert diluent, preferably nitrogen, to produce a pressurized gas source in a safe and useable concentration, currently in the range of 100 to 800 ppm of NO. Because this method uses cylinder concentrations in the parts per million (ppm) level it requires the use of large pressurized cylinders (approximately 175 mm diameter and 910 mm high with a wetted volume of 16 L and a weight of 18 Kg), which are bulky, heavy, and provide logistical problems and safety requirements associated with the handling of large pressurized gas cylinders. The cylinders are pressurized to 150 Bar and hold approximately 2000 L of useable gas. However, at a concentration of 800 ppm NO gas, the total drug quantity is 0.066 moles which weighs only 2 gms. Hence, it can be seen that the drug packaging represents 9,000 times the weight of the drug contained therein.
Nitric oxide readily combines with oxygen (O2) to form nitrogen dioxide (NO2), a known toxic gas, so it is very important that the gas cylinder does not become contaminated with oxygen. It is for this reason that the diluent gas used in the cylinders is one that is inert to, i.e. will not oxidize, nitric oxide. While a number of such inert gases are known, it is preferred to utilize nitrogen, N2, primarily on the basis of cost.
The delivery apparatus for dispensing gaseous NO has to deliver the NO source gas into the patient's respirable gas to give a concentration in the range of 1-80 ppm to the patient's lung in a precise and controllable manner. It also has to deliver it in a manner that minimizes the formation of NO2. The parameters that are relevant to the formation of NO2 are the square of the NO concentration, the O2 concentration and the time for the reaction between them to take place. The O2 concentration is not normally controllable by the NO delivery device and the source gas is at a fixed concentration, therefore, the time for the reaction to take place is the only variable.
Apparatus for the delivery of nitric oxide (NO) from a gas cylinder has to not only precisely deliver the correct dose of NO to the patient, but also to minimize the time from delivery to when the patient breathes in the gas to prevent the formation of NO2 at unsafe levels. An example of a bedside NO delivery device that achieves these two functions is described in U.S. Pat. No. 5,558,083 which shows how a constant concentration of NO can be delivered to a patient who is on a gas delivery system such as a ventilator. Smaller ambulatory NO delivery devices are described in U.S. Pat. No. 6,089,229, U.S. Pat. No. 6,109,260, U.S. Pat. No. 6,125,846, and U.S. Pat. No. 6,164,276, which describe how dosing can be provided in a pulse mode while keeping NO2 levels at an acceptably low level. While these pulse devices allow a compact and low weight delivery device to be made, they still require the bulk and weight of the NO cylinder for NO to be delivered.
Because of the challenges surrounding the current method of producing, distributing and safely administrating nitric oxide from pressurized cylinders to a patient, there have been a number of alternate solutions proposed to generate NO locally and to immediately deliver it to the patient. Some of those alternate solutions include using an electric arc discharge to produce NO from air prior to delivering it to a patient (U.S. Pat. No. 5,396,882): producing NO for inhalation by establishing a coulometric reduction of copper ions in a solution of nitric acid along with purging the chamber with an inert gas (U.S. Pat. No. 5,827,420); using a corona discharge to generate NO in a chamber that contains oxygen and nitrogen (EP 0719159); using a plasma chemical reaction method while heating the reaction chamber to 400-800° C. to obtain high efficiency of NO production (U.S. Pat. No. 6,296,827); and using heat to break down an organic nitrogen-containing compound, such as ammonia, to form NO (U.S. Pat. No. 6,758,214).
Each of the proposed solutions, however, has certain drawbacks in the generation of NO for direct delivery to the patient rather than having to handle the bulk and weight of pressurized gas cylinders and all of the proposed solutions fail to meet at least one of the requirements for a successful portable and safe NO generation system for the immediate delivery of NO to a patient. These requirements can include (1) compact size for easy handling (<100 mm×150 mm×50 mm); (2) low weight for easy portability (<2 Kgs), (3) no toxic compounds or byproducts that would raise safety concerns, (3) any reactants used should be readily available and not have any special storage or handling requirements, (4) low electrical power consumption so that battery operation is possible if necessary, (5) accurate, controllable generation of NO in just the amount needed for the patient and (6) fast generation so NO can be made and delivered to a patient without allowing NO2 to form.
Accordingly, it would be advantageous to have a method and device for the local generation of NO for immediate delivery to the patient and which overcomes the drawbacks and difficulties of the prior attempted solutions and which also possesses all of the desirable characteristics of such a system.